The invention, in some embodiments, relates to the field of receptor ligands, and more particularly to ligands for Somatostatin Receptors.
Somatostatin is an endogenous protein 116 amino acid residues long (SEQ ID NO:1) that is secreted, inter alia, in the brain, stomach, intestine and pancreatic delta cells which C-terminus is cleaved in vivo to make two circulatory active forms, SST-14 (14 amino acid residues, 103-116; SEQ ID NO:2):
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr- Ser-Cysand SST-28 (28 amino acid residues, 89-116; (SEQ ID NO:3):
Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu- Arg-Lys-(SST-14).
SST-14 and SST-28 are both ligands and agonists for a family of five G-protein coupled 7-transmembrane receptors called Somatostatin Receptors, SSTR1- SSTR5, collectively referred to as SSTRx herein. SSTRx are expressed in cells of healthy tissue and are also overexpressed in some pathological cells, including many different types of cancerous cells.
Both SST-14 and SST-28 act primarily as regulatory hormones by binding to the five SSTRx to be internalized into the cells expressing the SSTRx. As regulatory hormones, endogenous SST-14 and SST-28 are known to regulate other hormones of the endocrine system, affect neurotransmission, affect cell proliferation and inhibit the release of numerous hormones and secretory proteins from cells expressing SSTRx. Specifically, internalization of endogenous SST-14 and SST-28 into a cell expressing SSTRx potentially activates several signaling pathways that induce complex signaling cascades (e.g. inhibition of adenylate cyclase and cAMP production, activation of potassium ion channels, activation of a number of protein phosphatases from different families), the specific effect varying according to the SSTR subtype and the type of tissue type in which the cell is located. Further, a single cell or tissue type (both pathological and non-pathological cells and tissue) typically expresses more than one SSTRx subtype, and the relative proportion of the different SSTRx of a given cell can change over time and as a result of different conditions, including the development stage of the cell, exposure to non-Somatostatin hormones, neuropeptides and other biochemical stimuli.
To date, there exist two synthetic Somatostatin analogues approved for therapeutic use: Octreotide and Lanreotide, both display high-affinity binding to SSTR2, moderate affinity binding to SSTRR3 and SSTR5, and almost no affinity binding to SSTR1 and SSTR4
Lanreotide (commercially available in acetate form as Somatuline® by Ipsen Pharma S.A.S, Paris, France) is a synthetic Somatostatin analogue that is an octopeptide with a six-amino acid residue cyclic portion, having the amino acid residue sequence set forth in SEQ ID NO:4:
Napht-Cys*-Tyr-Trp-Lys-Val-Cys*-Thrwhere Napht is the alpha amino acid residue —NH—CH(CH2—C10H7)—C(O)O—(D-naphthylalanine D-Nal), and the asterisks indicate cyclization by an S—S bond between two cysteine amino acid residues. Lanreotide has been prescribed for treatment of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome.
Octreotide (commercially available in acetate form as Sandostatin® by Novartis, Basel, Switzerland) is a synthetic Somatostatin analogue that is an octopeptide with a six-amino acid residue cyclic portion, having the amino acid residue sequence set forth in SEQ ID NO:5:
DPhe-Cys*-Phe-DTrp-Lys-Thr-Cys*-Throlwhere Throl is the beta amino acid residue —NH—CH(CH2OH)—CH(CH3)—OH (L-threoninol) and the asterisks indicate cyclization by an S—S bond between the two amino acid residues.
Additional synthetic peptide Somatostatin analogues have been disclosed by one of the present Inventors in U.S. Pat. No. 7,700,717. A prominent such analogue (designated 3207) has amino acid residue sequence set forth in SEQ ID NO:6:
DPhe-Cys*-Phe-Trp-DTrp-Lys-Thr-Phe-GlyS2*-NH2and the peptide—fluorescent conjugate designated “86” thereof:
FITC-GABA-DPhe-Cys*-Phe-Trp-DTrp-Lys-Thr-Phe- GlyS2*-NH2which is also identified herein as “Compound 1”, where GlyS2 is the alpha-secondary amino acid residue —N(CH2CH2S—)CH2CO— (glycine with a —CH2CH2S— moiety added to the terminal amino group, as described in Gazal S et al J Pept Res 2001, 58(6), 527-539; which in the sequence listing is referred to as N-thioethyl Glycine), the asterisks indicate cyclization by a disulfide (S—S) bond between two amino acid residues, and FITC-GABA is a fluorescent active agent made up of the fluorophore FITC (fluorescein isothiocyanate) and the linker GABA (gamma-aminobutyric acid).
It would be useful to have therapeutically-active, stable and receptor-specific somatostatin analogues.